This proposal examines a novel, neuronal signaling pathway implicated in amyloid precursor protein (APP) processing. A? amyloid accumulates in brain as a defining aspect of Alzheimer's disease and is generated in the ?amyloidogenic pathway? via the sequential processing of APP by ? secretase (BACE1) and ?-secretase. APP is also processed by ?-secretase ADAM10 (a disintegrin and metalloprotease 10), which is termed the ?non-amyloidogenic? pathway since it prevents A? generation. While a great deal is known about BACE1 and ?-secretase, less is known about mechanisms that control ADAM10 processing of APP. We have discovered a signaling pathway that controls ADAM10 processing of APP in neurons, and in preliminary studies demonstrate its dysregulation in human Alzheimer's disease brain. This pathway includes plasma membrane proteins GDE2 (glycerophosphodiester phosphodiesterase 2), an enzyme that catalyzes cleavage of GPI (glycosylphosphatidylinositol) linked proteins; RECK (reversion-inducing cysteine-rich protein with Kazal motif, which is an inhibitor of ADAM10 and a GPI linked protein that is ?shed? from the plasma membrane by GDE2; and ADAM10. In support of the importance of this signaling pathway, Gde2 KO mice exhibit a pronounced reduction in ?-secretase cleavage products and a dramatic shift toward amyloidogenic processing of APP. Moreover, levels of membrane RECK are increased in Gde2 KO brain, and expression of membrane-tethered RECK is sufficient to inhibit endogenous ?-secretase activity in neurons. Preliminary studies examining human postmortem brain document biochemical and histochemical evidence of GDE2 loss of function and robust elevation of membrane RECK in Alzheimer's patients. We hypothesize that GDE2 control of RECK surface expression regulates ADAM10 ?-secretase activity and that disruption of this pathway shifts equilibrium of APP processing towards the amyloidogenic pathway. Aim 1 will define the mechanism of RECK inhibition of ADAM10 ?-secretase activity and will determine contributions to amyloidogenic APP processing. Aim 2 will test the hypothesis that GDE2 regulation of surface RECK expression is a critical determinant of ADAM10 ?- secretase function. Aim 3 will determine physiological contributions of GDE2 and RECK to the onset and progression of A? pathogenesis in new knock-in mouse models of amyloidosis. Our studies will determine if the GDE2-RECK pathway is a critical determinant of ADAM10 ?-secretase activity; outcomes could provide new molecular perspective into mechanisms of A? pathogenesis in human Alzheimer's disease.